ES2654474T3 - Nueva sal estable del ácido 5,10-metilen-(6R)-tetrahidrofólico - Google Patents

Nueva sal estable del ácido 5,10-metilen-(6R)-tetrahidrofólico Download PDF

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ES2654474T3
ES2654474T3 ES14758102.9T ES14758102T ES2654474T3 ES 2654474 T3 ES2654474 T3 ES 2654474T3 ES 14758102 T ES14758102 T ES 14758102T ES 2654474 T3 ES2654474 T3 ES 2654474T3
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methylene
tetrahydrofolic acid
stable salt
new stable
peaks
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Rudolf Moser
Viola Groehn
Thomas Egger
Thomas Ammann
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Merck et Cie
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Merck et Cie
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/12—Heterocyclic compounds containing pteridine ring systems containing pteridine ring systems condensed with carbocyclic rings or ring systems
    • C07D475/14—Benz [g] pteridines, e.g. riboflavin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

Sal hemisulfato del ácido 5,10-metilen-(6R)-tetrahidrofólico.

Description

imagen1
imagen2
imagen3
espectroscopia Raman infrarroja y otros métodos en estado sólido, como demuestran los datos proporcionados en este documento.
Por tanto, en una realización específica, la presente invención proporciona una forma cristalina de la sal hemisulfato anhidro de (6R)-5,10-CH2-THF (en adelante denominada también forma cristalina de tipo 1), caracterizada porque 5 proporciona:
(i) un patrón de difracción de rayos X por el método de polvo (DRXP) que proporciona espaciados reticulares calculados (expresado en 2θ ± 0,2° 2θ [radiación Kα de Cu]) en 4,7°; 17,9° y 23,3°, preferiblemente 4,7°; 16,6°; 17,9°; 18,4°; 18,9°; 20,2°; 23,3°; 23,5°; 24,3° y 24,7°; y/o
(ii) un espectro FT-Raman que contiene picos en números de onda (expresados en ±2 cm-1) de 1672, 1656, 1603, 10 1553, 1474, 1301, 637, 624 y 363 y/o
(iii) un espectro IR que tiene una o más bandas de absorción según la tabla 3.
En realizaciones preferidas, la sal hemisulfato (tipo 1) de la presente invención se caracteriza porque al menos 2 de los siguientes 10 picos de DRXP (expresados en 2θ ± 0,2° 2θ [radiación Kα de Cu]) en 4,7°; 16,6°; 17,9°; 18,4°; 18,9°; 20,2°; 23,3°; 23,5°; 24,3° y 24,7°; preferiblemente 4,7°; 17,9° y 23,3° y al menos 2 de los siguientes 9 picos de FT
15 Raman (expresados en ±2 cm-1) de 1672, 1656, 1603, 1553, 1474, 1301, 637, 624 y 363.
En otras realizaciones preferidas, la sal hemisulfato de (6R)-5,10-CH2-THF (tipo 1) de la presente invención proporciona un espectro FT-Raman sustancialmente de acuerdo con la figura 1 y/o picos como se recoge en la tabla 1 y/o un patrón de difracción de rayos X por el método de polvo (DRXP) sustancialmente de acuerdo con la figura 2(a) y/o picos como se recoge en la tabla 2.
20 Tabla 1:
Tabla de picos Raman (intensidad mf = muy fuerte, f = fuerte, m = media, d = débil, md = muy débil).
Número de onda [cm-1]
Intensidad (cualitativa)
3019
d
2933
m
2880
m
1672
f
1656
f
1603
mf
1553
m
1474
m
1373
m
1337
m
1301
f
5
1207
m
1127
d
975
m
884
m
815
d
700
d
665
d
637
f
624
f
363
m
Tabla 2: Tabla de picos de difracción de rayos X por el método de polvo expresados en 2θ ± 0,2° 2θ (radiación Kα de Cu) (intensidad mf = muy fuerte, f = fuerte, m = media, d = débil, md = muy débil).
Ángulo en 2θ °
Espaciados d en Å Intensidad (cualitativa)
4,7
18,8 mf
9,4
9,4
md
11,6
7,6 d
11,8
7,5 d
12,5
7,1 md
13,6
6,5 md
14,2
6,2 m
16,6
5,35 f
16,8
5,28 m
17,9
4,96 mf
6
18,4
4,83 f
18,9
4,68 f
20,2
4,38 f
21,0
4,23 d
21,7
4,09 d
23,3
3,82 mf
23,5
3,78 f
24,0
3,70 m
24,3
3,66 f
24,7
3,60 m
25,1
3,54 m
26,2
3,40 m
26,5
3,36 m
27,0
3,30 m
28,0
3,18 d
29,2
3,05 m
30,4
2,94 d
31,0
2,88 d
31,7
2,82 d
35,5
2,53 d
7
imagen4

Claims (1)

  1. imagen1
ES14758102.9T 2013-08-14 2014-08-14 Nueva sal estable del ácido 5,10-metilen-(6R)-tetrahidrofólico Active ES2654474T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13004050.4A EP2837631A1 (en) 2013-08-14 2013-08-14 New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid
EP13004050 2013-08-14
PCT/EP2014/067447 WO2015022407A1 (en) 2013-08-14 2014-08-14 Hemisulfate salt of 5,10-methylene-(6r)-tetrahydrofolic acid

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ES2654474T3 true ES2654474T3 (es) 2018-02-13

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ES17190279T Active ES2871483T3 (es) 2013-08-14 2014-08-14 Sal hemisulfato del ácido 5,10-metilen-(6r)-tetrahidrofólico
ES14758102.9T Active ES2654474T3 (es) 2013-08-14 2014-08-14 Nueva sal estable del ácido 5,10-metilen-(6R)-tetrahidrofólico

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Publication number Priority date Publication date Assignee Title
EP2837631A1 (en) * 2013-08-14 2015-02-18 Merck & Cie New stable salt of 5,10-methylene-(6R)-tetrahydrofolic acid
US10059710B2 (en) 2016-02-17 2018-08-28 Merck & Cie Stable formulations of 5,10-methylene-(6R)-tetrahydrofolic acid
EP3446704A1 (en) * 2017-08-24 2019-02-27 Isofol Medical AB [6r]-mthf - an efficient folate alternative in 5-fluorouracil based chemotherapy
EP3446703A1 (en) * 2017-08-24 2019-02-27 Isofol Medical AB 6r]-mthf multiple bolus administration in 5-fluorouracil based chemotherapy
WO2019034673A1 (en) 2017-08-16 2019-02-21 Merck Patent Gmbh STABLE LYOPHILISATES COMPRISING 5,10-METHYLENE- (6R) -TETRAHYDROFOLIC ACID AND DICARBOXYLIC ACID
EP3735267B8 (en) * 2018-01-05 2022-11-09 Isofol Medical AB Administration of multiple boluses of [6r] mthf in a 5-fluorouracil-based chemotherapy
KR20220152385A (ko) * 2020-03-30 2022-11-15 수미토모 케미칼 컴퍼니 리미티드 적층체
WO2023237485A1 (en) 2022-06-08 2023-12-14 Merck Patent Gmbh Stable lyophilisates comprising 5,10-methylene-(6r)-tetrahydrofolic acid
WO2023237484A1 (en) 2022-06-08 2023-12-14 Merck Patent Gmbh Compositions comprising disodium 5,10-methylene-(6r)-tetrahydrofolate
WO2023237482A1 (en) 2022-06-08 2023-12-14 Merck Patent Gmbh Concentrated solutions comprising sodium 5,10-methylene-(6r)- tetrahydrofolate
WO2023237483A1 (en) 2022-06-08 2023-12-14 Merck Patent Gmbh Concentrated solutions comprising 5,10-methylene-(6r)-tetrahydrofolic acid
WO2023237480A1 (en) 2022-06-08 2023-12-14 Merck Patent Gmbh Stable pharmaceutical compositions comprising 5,10-methylene-(6r)-tetrahydrofolic acid and nacl

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CH684644A5 (de) 1992-07-13 1994-11-15 Eprova Ag 5,10-Methylentetrahydrofolsäure-Cyclodextrin-Einschlussverbindungen.
HU226998B1 (en) * 2000-11-23 2010-04-28 Richter Gedeon Nyrt Desloratadine hemisulphate, process for the preparation thereof and pharmaceutical compositions containing the same
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CH697021A5 (de) * 2003-06-26 2008-03-31 Merck Eprova Ag Stabile pharmazeutische Zusammensetzungen von 5, 10-Methylentetrahydrofolat.
WO2007064968A2 (en) 2005-12-02 2007-06-07 Adventrx Pharmaceuticals, Inc. Stable pharmaceutical compositions of 5,10 methylenetetrahydrofolate
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